HIV-specific cytotoxic CD8+ T cell responses play an important protective role against HIV infection. A number of studies, however, have indicated that HIV-specific CDS+ T cells may be functionally impaired. In addition, we recently have shown that HIV-specific CDS+ T cells exhibit increased susceptibility to undergo CD95/Fas-mediated apoptosis. This is of particular importance as HIV upregulates FasL on infected cells, while at the same time inhibits CD95/Fas-mediated apoptosis of infected cells. Indeed we have recently shown that HIV-infected macrophages can induce apoptosis of HIV-specific CDS+ T cells and this is largely due to CD95/Fas-mediated apoptosis. Furthermore HIV-specific CDS+ T cells lack the terminally differentiated CD45RA+CD62L- effector memory phenotype and this may affect the function of these cells in vivo. We recently have found evidence that CD95/Fas-mediated apoptosis may be responsible for this lack of differentiation. Thus HIV, by manipulating CD95/Fas-induced apoptosis, may be setting up an intricate CTL evasion and counterattack mechanism. Enhancing effector function, differentiation and/or survival of HIV-specific CDS+ T cells would enhance the efficiency of HIV-specific CD8+ T cells to control or clear HIV virus. Interleukin 15 (IL-15) is a pluripotent cytokine that expands in vivo memory CD8+ T cells, enhances their survival, and inhibits CD95/Fas-induced apoptosis. To date, no in depth investigation has been carried out on the effect of IL-15 on HIV-specific CD8+ T cells. We hypothesize that IL-15 treatment can enhance cytotoxic CDS+ T cells immunity against HIV This hypothesis is based on the known effects of lL-15 on mouse memory CDS+ T cells, and our own preliminary data that show that IL-15 can inhibit apoptosis and enhance effector function of HIV-specific CDS+ T cells. We propose to investigate the in vitro effect of IL-15 on effector function, differentiation, proliferation, and apoptosis of HIV-specific CDS+ T cells. We will also investigate the potential mechanism of action of IL-15 by examining the ASK1 signaling pathway and also examining gene expression using gene arrays. The studies in this proposal are novel and will provide valuable information on potential approaches to enhance the CD8+ T cell response against HIV in infected individuals. Information yielded from these studies will fill a knowledge gap as to the effect of IL-15 on anti-viral cytotoxic CDS+ T cell responses, and may prove useful for both novel therapeutic strategies and vaccine development for HIV infection and other viral infections.